The basic goal continues to be to find exploitable biochemical differences between normal and cancer cells. Our major study systems include normal and regenerating rat liver and hepatomas as well as the four major types of human leukemic cells and normal leukocytes. We have described the high M.W. DNA polymerase (D.P.) and compared its properties to the low M.W. DP in liver tissues and we have found two seemingly analogous enzymes in nuclei of acute granulocytic leukemia (AGL). It is planned to complete the analysis of these leukemic enzymes in AGL cytoplasm and in CGL, ALL and CLL cells now that we have developed the complex methodology for enzyme isolation and assay. If the two DP's are identical in human leukemia and rat liver then we will use the latter enzymes to study the effects of certain possible DP inhibitors which are established or potential chemotherapeutic drugs: if there are enzymatic differences then we will rely on the cell separator to provide adequate leukemic material for enzyme preparation. We plan to expand the study of a newly discovered heat stable protein factor which stimulates the DP reaction--we will attempt to define its mechanism of action, its tissue specificity and its physical and chemical properties. A related study deals with the critical interaction of DNA with DP and with deoxynucleoside triphosphates in the DP reaction. It is intended to institute a comprehensive leukemic cell metabolism program which will permit us to study the effects of chemotherapeutic drugs on major metabolic pathways of intact cells, thence on the subcellular enzyme systems relevant to those effects. We will follow these in vitro leads as has been done previously in our laboratory with streptomycin, and to include the study of cells before and after single agent or combination chemotherapy.